CN114149500B - 抗人emc10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用 - Google Patents
抗人emc10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用 Download PDFInfo
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Abstract
本发明公开了抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用。本发明公开了抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用,所述单克隆抗体能特异性识别氨基酸序列如SEQ ID No.5所示的抗原表位。本发明提供的抗EMC10的单克隆抗体显著降低小鼠的肝脏重量和肝脏的脂肪浸润,可用于制备治疗和/或预防脂肪肝的产品,为脂肪肝提供了一个全新的治疗靶点。
Description
技术领域
本发明属于生物医药产业中的抗体药物,具体涉及抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝产品中的应用。
背景技术
在全球范围内,随着病毒性肝炎的控制,脂肪肝(fatty liver disease,FLD)逐步成为慢性肝病(chronic liver disease,CLD)发生发展的主要原因。FLD可从单纯的肝脂肪变性进展为脂肪性肝炎和肝纤维化,临床将FLD分为酒精性脂肪肝(alcoholic liverdisease,ALD)和非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD),其中NAFLD是欧洲国家近十年来因CLD进行肝移植的主要病因,也是美国和英国造成肝细胞癌的主要原因,影响着全球近25%人口的健康。在超声证实的NAFLD患者中,有6-30%经组织学检查可证实进展为了非酒精性肝炎(non-alcoholic steatohepatitis,NASH),而40%的NASH患者有着向肝纤维化进展的趋势。
除了造成肝脏本身的损伤以外,NAFLD会引起或者加剧胰岛素抵抗,还与代谢综合征(Metabolic syndrome,MetS)、2型糖尿病(Type 2diabetes mellitus,T2DM)、动脉粥样硬化等内分泌和心血管疾病息息相关。NAFLD患者患T2DM的风险是非NAFLD患者5倍。近90%的NAFLD患者至少有MetS的一种临床表现,约33%的患者可诊断为MetS。研究表明,至少有70%肝功能正常的T2DM患者同时存在NAFLD。此外,NAFLD也会增加冠状动脉粥样硬化、缺血性心脏病的风险,会增加颈动脉内膜中膜厚度,因此也被认为是心血管疾病新的独立危险因素。
目前仍然缺乏有效治疗NAFLD的药物,加强锻炼和饮食控制能有效较少肝脏脂肪含量、降低肝酶水平、改善代谢综合征症状,仍为首要的推荐治疗NAFLD的方法,但是对大多数患者来说难以长期坚持。
EMC10最初由从人胰岛素瘤组织的cDNA文库中克隆得到,当时命名为:INM02,INM02(EMC10)基因的核苷酸序列及其编码的氨基酸序列如GenBank数据库(登录号为:AY194293)(Wang XC,Xu SY,Wu XY,Song HD,Mao YF,Fan HY,Yu F,Mou B,Gu YY,Xu LQ,Zhou XO,Chen Z,Chen JL,Hu RM.Gene expression profiling in human insulinomatissue:genes involved in the insulin secretion pathway and cloning of novelfull-length cDNAs.Endocr Relat Cancer.2004,11:295-303.)。目前为止,已经有数项研究揭示了EMC10的多种生物学功能。利用Wang X等人建立的ELISA方法,我们在国际上首次报导了EMC10是一个在人血清中可以被检测得到的分泌蛋白,并且发现在小鼠胰岛β细胞中Emc10(Inm02)基因的表达受葡萄糖的调控,提示它在糖代谢中可能发挥重要的作用(WangX,Gong W,Liu Y,Yang Z,Zhou W,Wang M,Yang Z,Wen J,Hu R.Molecular cloning of anovel secreted peptide,INM02,and regulation of its expression by glucose.JEndocrinol.2009,202:355-364.)。之后另一个研究小组报道从人纯化的造血干细胞中克隆到了EMC10,该研究小组将其命名为HSS1,并将其另一个剪切异构体命名为HSM1;同时他们在体外研究发现,EMC10(HSS1)能够抑制胶质瘤细胞株的增殖、迁移、侵袭,同时也能够抑制内皮细胞的新生血管形成,因此他们认为EMC10是治疗恶性胶质母细胞瘤潜在的靶点(Junes-Gill KS,Gallaher TK,Gluzman-Poltorak Z,Miller JD,Wheeler CJ,Fan X,Basile LA.hHSS1:a novel secreted factor and suppressor of glioma growthlocated at chromosome 19q13.33.J Neurooncol.2011,102(2):197-211.;Junes-GillKS,Lawrence CE,Wheeler CJ,Cordner R,Gill TG,Mar V,Shiri L,Basile LA.HumanHematopoietic Signal peptide-containing Secreted 1(hHSS1)modulates genes andpathways in glioma:implications for the regulation of tumorigenicity andangiogenesis.BMC Cancer.2014,14:920.)。还有研究发现,在一个精神分裂小鼠模型中,升高的Mrita22(人EMC10的小鼠同源基因)能够抑制神经元细胞树突和脊突的发育,通过降低Mrita22的水平能够完全挽救上述小鼠模型海马椎体神经元树突和脊突发育的缺陷,提示EMC10在小鼠神经元树突和脊突形成过程中发挥重要作用(Xu B,Hsu PK,Stark KL,Karayiorgou M,Gogos JA.Derepression of a neuronal inhibitor due to miRNAdysregulation in a schizophrenia-related microdeletion.Cell.2013,152(1-2):262-75.;Diamantopoulou A,Sun Z,Mukai J,Xu B,Fenelon K,Karayiorgou M,GogosJA.Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion.Proc Natl AcadSci U S A.2017;114(30):E6127-E6136.)。最近来自德国的研究者发现,在一个心肌梗塞的小鼠模型,Emc10缺失导致梗塞边缘区的血管新生减少,左心室收缩和舒张功能受损,给予心肌梗塞小鼠补充EMC10能够增加梗塞边缘区的血管新生,改善心梗后受损的左室功能,提示EMC10是一个心肌梗塞后促进组织修复的具有血管新生功能的生长因子(Reboll MR,Korf-Klingebiel M,Klede S,Polten F,Brinkmann E,Reimann I,HJ,Bobadilla M,Faix J,Kensah G,Gruh I,Klintschar M,Gaestel M,Niessen HW,Pich A,Bauersachs J,Gogos JA,Wang Y,Wollert KC.EMC10(Endoplasmic Reticulum MembraneProtein Complex Subunit 10)Is a Bone Marrow-Derived Angiogenic Growth FactorPromoting Tissue Repair After Myocardial Infarction.Circulation.2017;136(19):1809-1823.)。Zhou Y等人研究发现,EMC10缺失导致雄性小鼠不育,缺少Emc10基因的精子表现出多方面的缺陷,包括形态学的异常、精子运动力减弱、精子获能受损、顶体反应缺失。分子机制研究发现EMC10缺失导致钠/钾-ATP酶失活以及HCO3-诱导的cAMP/PKA信号通路激活受损和精子获能相关蛋白酪氨酸磷酸化水平的下降(Zhou Y,Wu F,Zhang M,Xiong Z,Yin Q,Ru Y,Shi H,Li J,Mao S,Li Y,Cao X,Hu R,Liew CW,Ding Q,Wang X,ZhangY.EMC10 governs male fertility via maintaining sperm ion balance.J Mol CellBiol.2018Dec 1;10(6):503-514.)。
尽管有这些研究进展,EMC10与脂肪肝间是否存在关系还没有报道。
发明内容
本发明所要解决的技术问题为如何治疗和/或预防脂肪肝。
为解决上述技术问题,本发明首先提供了抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用。
本发明所提供的抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用中,所述抗人EMC10的单克隆抗体的名称为4C2,所述单克隆抗体能特异性识别氨基酸序列如SEQ ID No.5所示的抗原表位,即VVGVSVVTHP。
上述应用中,所述抗人EMC10的单克隆抗体含有名称为VH的重链可变区和名称为VL的轻链可变区,所述VH和VL均由决定簇互补区和框架区组成;所述VH和所述VL的决定簇互补区均由CDR1、CDR2和CDR3组成;
所述VH的CDR1的氨基酸序列如SEQ ID No.1的第31-35位所示;
所述VH的CDR2的氨基酸序列如SEQ ID No.1的第50-68位所示;
所述VH的CDR3的氨基酸序列如SEQ ID No.1的第101-103位所示;
所述VL的CDR1的氨基酸序列如SEQ ID No.2的第24-39位所示;
所述VL的CDR2的氨基酸序列如SEQ ID No.2的第55-61位所示;
所述VL的CDR3的氨基酸序列如SEQ ID No.2的第94-102位所示。
上述应用中,所述VH和VL的框架区均来源于小鼠。
上述应用中,所述VH的氨基酸序列可如SEQ ID No.1所示;所述VL的氨基酸序列可如SEQ ID No.2所示。
其中,SEQ ID No.1由114个氨基酸残基组成,SEQ ID No.2由113个氨基酸残基组成。
上述应用中,所述抗人EMC10的单克隆抗体可为下述任一种:
S1)由所述VH和所述VL连接得到的单链抗体;
S2)含有S1)所述单链抗体的融合抗体;
S3)含有所述VH和所述VL的Fab;
S4)含有所述VH和所述VL的完整抗体;
S5)由保藏号为CGMCC No.19950的杂交瘤细胞株4C2分泌的单克隆抗体。
上述应用中,所述抗人EMC10的单克隆抗体可为鼠源单克隆抗体。
与上述单克隆抗体相关的生物材料在制备治疗和/或预防脂肪肝的产品中的应用也在本发明的保护范围之内;所述生物材料可为下述中的任一种:
A1)编码所述单克隆抗体的核酸分子;
A2)含有A1)所述核酸分子的表达盒;
A3)含有A1)所述核酸分子的重组载体、或含有A2)所述表达盒的重组载体;
A4)含有A1)所述核酸分子的重组微生物、或含有A2)所述表达盒的重组微生物、或含有A3)所述重组载体的重组微生物。
上述应用中,所述核酸分子可以是DNA,如cDNA、基因组DNA或重组DNA;所述核酸分子也可以是RNA,如mRNA或hnRNA等。
上述应用中,A1)所述核酸分子为编码所述单克隆抗体的基因,所述基因可为如下B1)或B2)所述的DNA分子:
B1)所述VH的CDR1的编码序列如SEQ ID No.3的第91-105位所示,所述VH的CDR2的编码序列如SEQ ID No.3的第148-204位所示,所述VH的CDR3的编码序列如SEQ ID No.3的第301-309位所示;所述VL的CDR1的编码序列如SEQ ID No.4的第70-117位所示,所述VL的CDR2编码序列如SEQ ID No.4的第163-183位所示,所述VL的CDR3的编码序列如SEQ IDNo.4的第280-306位所示;
B2)与B1)限定的DNA分子具有90%以上的同一性且编码所述单克隆抗体或其抗原结合部分的DNA分子。
其中,SEQ ID No.3由342个核苷酸组成,SEQ ID No.4由339个核苷酸组成。
上述应用中,“同一性”指与天然核酸序列的序列相似性。同一性可以用肉眼或计算机软件进行评价。使用计算机软件,两个或多个序列之间的同一性可以用百分比(%)表示,其可以用来评价相关序列之间的同一性。
上述应用中,90%以上的同一性可为至少91%、92%、95%、96%、98%或99%的同一性的DNA分子。
上述应用中,A2)所述的表达盒,是指能够在宿主细胞中表达所述单克隆抗体或其抗原结合部分的DNA,该DNA不但可包括启动所述单克隆抗体或其抗原结合部分基因转录的启动子,还可包括终止所述单克隆抗体或其抗原结合部分基因转录的终止子。进一步,所述表达盒还可包括增强子序列。可用现有的表达载体构建含有所述单克隆抗体基因表达盒的重组载体。
上述应用中,所述重组载体可为质粒、黏粒、噬菌体或病毒载体。
上述应用中,所述重组微生物可为酵母、细菌、藻或真菌。
上述单克隆抗体或生物材料在下述任一中的应用也在本发明的保护范围之内:
C1)在制备降低动物的肝脏的脂肪浸润的产品中的应用;
C2)在制备降低动物的血清甘油三酯含量的产品中的应用;
C3)在制备降低动物的血清游离脂肪酸含量的产品中的应用;
C4)在制备降低动物的血清胆固醇含量的产品中的应用。
为解决上述技术问题,本发明进一步还提供了一种治疗和/或预防脂肪肝的方法。
本发明所提供的治疗和/或预防脂肪肝的方法包括给受体动物施用上述单克隆抗体。
上文中,所述产品可以为药物、疫苗、试剂或试剂盒。
上文中,所述动物为哺乳动物,如小鼠或人。
本发明中所述治疗和/或预防脂肪肝主要体现在降低肝脏的脂肪浸润、降低血清胰岛素含量、降低血清甘油三酯含量、降低血清游离脂肪酸含量、降低血清胆固醇含量和提高胰岛素敏感性等方面。
本发明脂肪肝具体指非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)。
本发明提供的抗EMC10的单克隆抗体显著降低小鼠的肝脏重量和肝脏的脂肪浸润,可用于制备治疗和/或预防脂肪肝的产品,为脂肪肝提供了一个全新的治疗靶点。
保藏说明
参据的生物材料(株):4C2
建议的分类命名:小鼠抗人EMC10单克隆抗体杂交瘤细胞株
保藏机构:中国微生物菌种保藏管理委员会普通微生物中心
保藏机构简称:CGMCC
地址:北京市朝阳区北辰西路1号院3号
保藏日期:2020年6月18日
保藏号:CGMCC No.19950
附图说明
图1为采用Dot blot的方法鉴定纯化蛋白的结果图,图中,1-9分别代表蛋白的重量为30、15、7.5、3.75、1.875、0.9375、0.46875、0.234375、0.1171875ng。
图2为采用Western blot的方法鉴定纯化蛋白的结果图。
图3为小鼠EMC10蛋白和不同鼠抗人EMC10的单克隆抗体同时干预HeLa细胞后的CREB的磷酸化水平结果图;图中,Ctr表示只含EMC10蛋白,无EMC10抗体;1、2、3、4分别表示含有1F12、4B12-1、4B12-2、4C2抗体,同时含有EMC10蛋白。
图4为抗Flag标签的抗体western blot检测野生型和不同截短体的EMC10蛋白的结果,图中,WT表示野生型,即EMC10蛋白;Δ28-105、Δ66-145、Δ106-183、Δ146-225、Δ184-254、Δ146-175、Δ171-200、Δ196-225、Δ146-155、Δ156-165、Δ166-175缺失了28-105、66-145、106-183、146-225、184-254、146-175、171-200、196-225、146-155、156-165、166-175氨基酸的EMC10截短体。
图5为抗人EMC10的单克隆抗体4C2对饮食诱导的肥胖小鼠的体重及脂肪肝的影响;其中,A和B分别为对照IgG组、1F12和4C2抗体组的小鼠体重增长和体重增加的情况;C为对照IgG组、1F12和4C2抗体组的小鼠的肝脏重量;D为HE染色观察肝脏组织中脂质浸润的情况;图中,*P<0.05,***P<0.001,****P<0.0001。
图6为抗人EMC10的单克隆抗体4C2对高脂饮食小鼠脂肪肝伴随的代谢紊乱的影响;其中,A-E分别为对照IgG组、1F12和4C2抗体组的小鼠胰岛素耐量、血清中胰岛素、甘油三酯、非酯化的脂肪酸以及胆固醇的检测结果;图中,*P<0.05。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1抗人EMC10的单克隆抗体4C2的获得及其在治疗小鼠的脂肪肝并改善其伴随的代谢紊乱的应用
本实施例用鼠抗人EMC10的单克隆抗体对肥胖小鼠进行干预,观察是否能够改善脂肪肝及其伴随的代谢紊乱。
一、鼠抗人EMC10的单克隆抗体的获得
(一)、鼠抗人EMC10单克隆抗体的制备
制备了8株小鼠抗人EMC10的单克隆抗体。具体步骤如下:
1、构建EMC10真核表达重组质粒
构建重组质粒pRAG2a-EMC10:用SEQ ID NO.7第82-762位所示DNA片段替换真核表达载体pRAG2a的酶切位点NheⅠ与XhoⅠ之间的小片段,得到重组质粒pRAG2a-EMC10。
2、转染与表达
(1)培养>1×108HEK 293F细胞备用。
(2)用稀释液(Opti-MEM)将100μg重组质粒pRAG2a-EMC10稀释到1ml,轻轻的混匀。
(3用稀释液(Opti-MEM)稀释200μl LipofectamineTM2000脂质体终体积至1ml。轻轻混匀,室温放置5min。
(4)将稀释后的质粒加入到稀释好的LipofectamineTM2000脂质体中,使其混合物终体积为2ml,轻轻混匀。
(5)室温孵育30min。
(6)转移1×108HEK 293F细胞到500ml摇瓶中,加入新鲜、预热的ExpressionMedium使其终体积至98ml。
(7)加入2ml孵育后的DNA-LipofectamineTM2000混合物。
(8)8%CO2浓度的培养箱内,37℃、125rpm培养4-5天。
(9)4℃,收集上清。上清中含有切除了信号肽的EMC10成熟蛋白(如序列表的SEQID NO.6的第28-254位所示)。
3、纯化蛋白及SDS-PAGE鉴定
(1)取步骤2的(9)得到的上清,加入binding buffer(8M尿素,20mM磷酸钠,500mMNaCl,pH 7.8),然后用0.45μm滤膜过滤,收集滤液。
(2)平衡:5个柱体积的binding buffer平衡镍柱。
(3)上样:步骤(1)得到的滤液上样。
(4)洗杂:5个柱体积binding buffer洗杂,直至流穿无物质流出。
(5)洗脱:5个柱体积elution buffer(8M尿素,20mM NaH2PO4,500mM NaCl,pH 4.0)洗脱,收集洗脱产物。
(6)SDS-PAGE检测。
仅显示一条36KD左右的条带,表明得到了电泳纯的目的蛋白。
4、Dot blot与Western blot鉴定
(1)、采用Dot blot的方法鉴定步骤3得到的纯化蛋白。采用的抗EMC10的抗体为兔抗人EMC10多克隆抗体(用序列表的SEQ ID NO.6所示EMC10蛋白作为免疫原免疫新西兰大白兔后得到的多克隆抗体);二抗为山羊抗兔的HRP抗体(Thermo Fisher,Catalog#65-6120)。
结果如图1所示。由图可见,2000倍稀释,样本蛋白稀释到约0.47ng有阳性结果(7号);约0.23ng无阳性结果(8号)。
(2)、采用Western blot的方法鉴定步骤3得到的纯化蛋白。采用的抗EMC10的抗体为兔抗人EMC10多克隆抗体(用序列表的序列6所示EMC10蛋白作为免疫原免疫新西兰大白兔后得到的多克隆抗体);二抗为山羊抗兔的HRP抗体(Thermo Fisher,Catalog#65-6120)。
结果如图2所示。由图可见,10ng样本上样,在36KD左右有阳性条带。
Dot blot与Western blot鉴定的结果表明EMC10蛋白真核表达成功。
5、动物免疫
选取6只6-8周龄雌性BALB/c小鼠,将步骤3得到的纯化蛋白与弗氏完全佐剂体积比1:1混合首次免疫,皮下注射100μg,每2-3周加强免疫一次,采用混合剂皮下注射100μg。四免后采血检测,通过间接ELISA法测定抗血清针对EMC10蛋白的效价(效价用样品孔OD值/阴性孔OD值≥2.1的血清的最大稀释倍数表示),待效价大于1:10000,选择1-2只小鼠进行细胞融合安排。
上述间接ELISA法测定抗血清针对EMC10蛋白的效价的步骤具体如下:
(1)包板:吸取自行制备的标准品EMC10(在实施例1的步骤3中表达纯化)的溶解在0.1M PBS缓冲液中,制成浓度为1μg/ml的包被溶液,100μl/孔,4℃包被过夜。
(2)洗板:弃去孔内液体,甩干,洗板2次,每次浸泡1-2分钟,大约200μL/每孔,甩干并在吸水纸上轻拍将孔内液体拍干。
(3)封闭:封闭液250μl/孔,37℃,2h。
(4)洗板:弃去孔内液体,甩干,洗板5次,方法同步骤(2)。
(5)检测:吸取待测血清溶解在抗体稀释液(0.1M PBS)中,制成稀释倍数为1000、3000、9000、27000倍的工作液,每孔加不同浓度的工作液100μL,注意不要有气泡,加样时加于酶标板底部,尽量不触及孔壁,轻轻晃动混匀。给酶标板覆膜,37℃孵育2h。
(6)洗板:弃去孔内液体,甩干,洗板5次,方法同步骤(2)。
(7)每孔加入兔抗鼠-HRP 100μL,加上覆膜,37℃温育1小时。
(8)弃去孔内液体,甩干,洗板5次,方法同步骤(2)。
(9)显色:底物显色A、B液1:1(体积比)混合后,每孔加100μL,酶标板加上覆膜,37℃避光孵育15分钟。
(10)每孔加终止液50μL,终止反应,此时蓝色立转黄色。终止液的加入顺序应尽量与底物溶液的加入顺序相同。
(11)立即用酶标仪在450/630nm双波长测量各孔的光密度(OD值),并读数。应提前打开酶标仪电源,预热仪器,设置好检测程序。
(12)结果判断:样品孔OD值/阴性孔(即空白对照孔)OD值≥2.1时为阳性。结果显示血清抗EMC10抗体稀释倍数大于10,000的样品孔为阳性,说明抗体效价大于1:10000。
6、细胞融合
(1)骨髓瘤细胞制备:融合前一周,用含10%FBS DMEM培养基扩大培养SP2/0细胞。到融合时,细胞长满大约6瓶T25细胞培养瓶,在融合当天收集SP2/0细胞到50ml离心管中,1000rpm,5min离心。弃上清,然后再加入20ml DMEM基础培养基,吹散细胞然后计数。
(2)脾细胞制备:四次免疫后血清ELISA效价在1:10000以上的小鼠,在融合前3天终免,腹腔注射步骤三纯化后的EMC10蛋白与弗氏完全佐剂体积比1:1混合剂100μg。融合当天用颈椎脱臼法安乐死要融合的小鼠。用75%酒精浸泡5min。无菌取脾脏,把脾脏放入内有10ml DMEM基础培养的培养皿中。取筛网放入另一个平皿中,将脾脏转移到筛网上,用注射器内心研磨脾脏。加入DMEM到筛网上,冲洗筛网,使脾细胞更多的收集到平皿中。将细胞移至10ml离心管中,用不含血清的DMEM洗脾细胞两次,1000rpm离心5min,收集脾细胞计数。
(3)细胞融合:混合骨髓瘤细胞和脾细胞,使骨髓瘤细胞同脾细胞数量比在1:20为宜。把细胞放到50ml离心管中,用DMEM基础培养基稀释,然后离心1000rpm5min。弃上清。摇动离心管使细胞均匀。缓慢加入0.8ml 50%PEG,反应90秒,然后加入20-30ml DMEM培养基终止PEG。把融合的细胞放到37℃水浴锅中反应10分钟。1000rpm 5min离心,弃上清然后加入HAT DMEM培养基。把融合的细胞铺到96孔板中,每孔100μl。然后将细胞培养板放到CO2培养箱中培养。
融合后4天查看,杂交瘤细胞克隆率在50%以上,有少量的细胞碎片,细胞生长状态良好。融合10天后开始进行筛选检测。
7、融合筛选及亚克隆
(1)融合筛选:在检测的前一天,用PBS包被5μg/ml抗原(步骤三纯化后的EMC10蛋白)于ELISA板,过夜。次日吸取细胞上清100μl/孔进行ELISA检测,根据ELISA结果,判断阳性孔(样品孔OD值/阴性孔(空白对照孔)OD值≥2.1,则判定为阳性孔)。用单道移液器挑检整板检测出的阳性孔,进行第二次确认检测,进一步确认阳性孔。确定后的阳性孔细胞进行亚克隆。
(2)亚克隆:吹打阳性孔中细胞,计数,在离心管中加入4ml DMEM培养基,取100μl细胞悬液到离心管中,吹匀后留1ml,补加DMEM到4ml,吹匀,留100μl(约2滴)在管底。在离心管中加DMEM至5ml,混匀后滴加至96孔板的前三行,每孔一滴管底留1.8-2ml左右,补加DMEM至5ml,吹匀后滴加至96孔板的D、E、F三行,每孔一滴,管底留1.5-1.8ml左右,补加DMEM至2.8-3ml左右,吹匀后滴加至96孔板的G、H行,每孔一滴,7-10天后在显微镜下观察,检测有克隆生长的孔,标记出单克隆的孔,尽可能挑取阳性的单克隆细胞进行再次亚克隆,检测至100%阳性后,挑出单克隆孔扩大培养定株。
最终获得8个能够稳定分泌抗EMC10蛋白的单克隆抗体的杂交瘤细胞株,分别编号为8C11、6B9、1F12、4B12-1、1H11、4C2、4B12-2和8A3。
8、腹水制备及纯化
(1)腹水制备:每只小鼠腹腔内注射0.5ml液体石蜡,7天后30天以内向预处理过的小鼠腹腔内注射杂交瘤细胞。按每只小鼠注射1×106个细胞的量,注射杂交瘤细胞。7至10天,用注射器针头小心从腹腔采出尽可能多的液体,并间接ELISA法进行效价测定(效价用样品孔OD值/阴性孔OD值≥2.1的血清的最大稀释倍数表示,阴性孔为空白对照)。小鼠在最后一次采集后颈椎脱位法处死。
(2)纯化:将所收集的腹水离心取上清,准备好蛋白A琼脂糖介质并装柱,将腹水用PBS稀释10倍后缓慢上样,上样结束后用磷酸盐缓冲液洗涤至紫外检测仪达到最低值,甘氨酸洗脱缓冲液洗脱,即得到所需纯化抗体,立即在PBS中进行4℃透析过夜,隔日进行纯度,浓度和效价测定(效价用样品孔OD值/阴性孔OD值≥2.1的血清的最大稀释倍数表示,阴性孔为空白对照)。
用1ug/ml的小鼠EMC10蛋白和1ug/ml的不同鼠抗人EMC10的单克隆抗体(1F12、4B12-1、4B12-2和4C2)同时干预HeLa细胞,利用western blotting检测CREB的磷酸化水平(前期研究显示EMC10能够抑制CREB的磷酸化),结果如图3所示,可见EMC10蛋白使CREB的磷酸化降低,4B12-1和4C2抗体能够使原本下降的CREB磷酸化回复到EMC10蛋白干预前,说明4B12-1和4C2抗体可以阻断EMC10蛋白的效应,而1F12和4B12-2却不能改变EMC10蛋白导致的CREB磷酸化下降,说明此两种抗体不能阻断EMC10蛋白的效应,结果:筛选出了2株能够阻断小鼠EMC10蛋白生物学效应的鼠抗人EMC10的单克隆抗体:4B12-1和4C2,1F12不能够阻断小鼠EMC10蛋白生物学效应作为对照抗体。
western blotting方法如下:
将1ug/ml的小鼠EMC10蛋白和1ug/ml的不同鼠抗人EMC10的单克隆抗体(1F12、4B12-1、4B12-2和4C2)加入培养液中干预HeLa细胞6小时,抽提细胞总蛋白,在12%的十二烷基硫酸钠-聚丙烯酰胺胶上电泳分离,再转移到聚偏二氟乙烯(PVDF)膜上,然后用兔抗p-CREB单克隆抗体(CST,货号:9198,1:1000稀释)、兔抗CREB1单克隆抗体(ABclonal,货号:A10826,1:1000稀释)和兔抗α-Tubulin多克隆抗体(CST,货号:2144,1:2000稀释)孵育,二抗采用辣根过氧化物酶耦联的山羊抗兔抗体(Sigma)(稀释度是1:10000),最后通过ECLPlus(Amersham)化学发光显示目的条带。
分泌鼠抗人EMC10的单克隆抗体4C2(以下简称4C2抗体)的单克隆杂交瘤细胞株4C2—小鼠抗人EMC10单克隆抗体杂交瘤细胞株4C2(以下简称4C2杂交瘤细胞或4C2细胞)已于2020年6月18日保藏于中国微生物菌种保藏管理委员会普通微生物中心(简称CGMCC,地址为:北京市朝阳区北辰西路1号院3号),保藏编号为CGMCC No.19950。
(二)、鼠抗人EMC10单克隆抗体4C2的序列
1.4C2杂交瘤细胞总RNA抽提
利用Trizol Reagent(Thermofisher,USA)抽提4C2细胞样品的总RNA,Nanodrop测定上述总RNA样品的浓度,共得到15μg总RNA(浓度:511.3ng/μL,体积:30μL,A260/A280=2.01),取500ng进行琼脂糖凝胶电泳分析,结果显示总RNA样品中28S和18S条带清晰可见,且28S条带亮度大于18S,表明两种RNA的完整性较好。
2、Mouse抗体片段扩增与序列分析
分别在抗体重链(mouse IgG1亚型)和轻链(kappa)的恒定区设计特异性引物,引物序列如下:Mouse IgG1 CH outer(5’~3’):ACAATCCCTGGGCACAAT,Mouse CL-Kappaouter(5’~3’):ACACTCATTCCTGTTGAAGCTCTTGAC。利用5’RACE分别扩增抗体重链片段和轻链片段。将扩增得到的片段插入克隆载体pUC57(Addgene,USA),进行测序,测序结果表明鼠抗人EMC10单克隆抗体4C2的重链可变区(VH)的编码基因序列是SEQ ID No.3,VH的氨基酸序列是SEQ ID No.1,其中,VH的CDR1的氨基酸序列如SEQ ID No.1的第31-35位所示,VH的CDR2的氨基酸序列如SEQ ID No.1的第50-68位所示,VH的CDR3的氨基酸序列如SEQ ID No.1的第101-103位所示;鼠抗人EMC10单克隆抗体4C2的轻链可变区(VL)的编码基因序列是SEQID No.4,VL的氨基酸序列是SEQ ID No.2,其中,VL的CDR1的氨基酸序列如SEQ ID No.2的第24-39位所示,VL的CDR2的氨基酸序列如SEQ ID No.2的第55-61位所示,VL的CDR3的氨基酸序列如SEQ ID No.2的第94-102位所示。
3、真核表达载体构建
将SEQ ID No.3所示的重链片段VH的编码基因与mouse IgG1的重链片段恒定区(CH)的编码基因拼接,插入到真核表达载体pAH(HAS Bind,Wuhai,China)中,得到抗体重链表达质粒pAH-4C2;将SEQ ID No.4所示的轻链片段(VL)的编码基因与mouse CL-kappa片段(轻链片段恒定区)的编码基因拼接,插入到真核表达载体pAK(HAS Bind,Wuhai,China)中,得到抗体轻链表达质粒pAK-4C2。对抗体重链表达质粒pAH-4C2采用正向和反向测序引物进行双向测通,然后进行序列比对分析;对抗体轻链表达质粒pAK-4C2采用正向测序引物测通,然后进行序列比对分析,得到重链的核苷酸序列如SEQ ID No.8所示(包含分泌信号肽的编码序列),表达SEQ ID No.9所示的蛋白质(第1-21位为分泌信号肽的氨基酸序列,第22-459位为鼠抗人EMC10单克隆抗体4C2重链的氨基酸序列);轻链的核苷酸序列如SEQ IDNo.10所示(包含分泌信号肽的编码序列),表达SEQ ID No.11所示的蛋白质(第1-21为分泌信号肽的氨基酸序列,第22-240位为鼠抗人EMC10单克隆抗体4C2轻链的氨基酸序列)。
4.抗体的真核表达与检测
将上述两种真核表达质粒(抗体重链质粒pAH-4C2和抗体轻链质粒pAK-4C2)进行中抽后(Plasmid Midiprep kit,AxyPrep,USA),通过琼脂糖凝胶电泳检测质粒质量。将抗体重链质粒pAH-4C2和抗体轻链质粒pAK-4C2共转染40mL HEK 293F细胞,表达结束后,收集细胞悬浮培养上清。为了评估和确认表达抗体的活性,将表达上清与4C2抗体(小鼠抗人EMC10单克隆抗体杂交瘤细胞株分泌的鼠抗人EMC10的单克隆抗体4C2)同步进行梯度稀释ELISA分析,结果如表1和表2所示:表达上清稀释约30倍的ELISA值与4C2抗体11ng/mL相当。
表1表达上清梯度稀释ELISA检测
表2 4C2抗体浓度梯度稀释ELISA检测
因此,确认小鼠抗人EMC10单克隆抗体杂交瘤细胞株分泌的鼠抗人EMC10的单克隆抗体4C2的重链可变区的氨基酸序列如SEQ ID No.1所示(编码序列如SEQ ID No.3所示),轻链可变区的氨基酸序列如SEQ ID No.2所示(编码序列如SEQ ID No.4所示)。所述重链可变区和轻链可变区均由决定簇互补区和框架区组成;所述重链可变区的决定簇互补区由CDR1(SEQ ID No.1的第31-35位所示,编码序列如SEQ ID No.3的第91-105位所示)、CDR2(SEQ ID No.1的第50-68位所示,编码序列如SEQ ID No.3的第148-204位所示)和CDR3(SEQID No.1的第101-103位所示,编码序列如SEQ ID No.3的第301-309位所示)组成;所述轻链可变区的决定簇互补区由CDR1(SEQ ID No.2的第24-39位所示,编码序列如SEQ ID No.4的第70-117位所示)、CDR2(SEQ ID No.2的第55-61位所示,编码序列如SEQ ID No.4的第163-183位所示)和CDR3(SEQ ID No.2的第94-102位所示,编码序列如SEQ ID No.4的第280-306位所示)组成。
下文实验中的鼠抗人EMC10单克隆抗体4C2均为小鼠抗人EMC10单克隆抗体杂交瘤细胞株分泌的鼠抗人EMC10的单克隆抗体4C2。
(三)、鼠抗人EMC10单克隆抗体4C2的抗原表位序列
分别将去掉信号肽的EMC10蛋白(包含28-254个氨基酸)分为5个不同的截短体,分别是缺失了28-105(Δ28-105)、66-145(Δ66-145)、106-183(Δ106-183)、146-225(Δ146-225)和184-254氨基酸(Δ184-254)的EMC10截短体(图4中A所示),利用4C2抗体去免疫共沉淀(IP)上述不同的截短体,再用抗Flag抗体进行western blotting检测,发现4C2抗体不能将缺失了第146-225位氨基酸的EMC10截短体(Δ146-225)IP下来(图4中A所示),说明4C2抗体针对的抗原表位在EMC10蛋白的146-225位氨基酸这个区域;接着再针对146-225位氨基酸构建了3个不同的截短体,分别是缺失了146-175(Δ146-175)、171-200(Δ171-200)和196-225氨基酸(Δ196-225)的EMC10截短体(图4中B所示),进行上述同样的实验,将抗原表位再次缩小至第146-175位氨基酸的区域(图4中B所示);重复上述的研究,最终确定4C2抗体针对的抗原表位在156-165区域(图4中C所示),这一区域所对应的EMC10蛋白氨基酸序列为:VVGVSVVTHP。
EMC 10抗原表位获得实验:
(1)利用PCR扩增出C端带有Flag标签的EMC10野生型(WT)和不同截短体(如图4)的基因序列,构建至不带标签的pLEX-MCS载体(Thermo Scientific)上。
(2)准备293T细胞在10厘米培养皿中,换无血清的DMEM培养液(Gibco),将野生型和不同截短体的EMC10质粒转染进293T细胞中,5小时后换含10%胎牛血清(Gibco)的DMEM培养液,1天后换液。
(3)再过1天后,用400ul EBC buffer(50mM Tris-HCl pH=7.5,120mM NaCl,0.5%NP-40)收集细胞,裂解,4℃12000rpm离心10min,收集上清液。
(4)在上清液中加入2ug抗人EMC10的单克隆抗体4C2(具体制备方法如步骤一),4℃共孵育4h。
(5)加入protein A/G agarose(Santa Cruz Biotechnology),4℃共孵育1h,用PBS洗beads。
(6)加入含SDS的1X loading(Beyotime),100℃煮样5min,变性,抗Flag标签的抗体(Cell Signaling Technology)western blot检测野生型(即EMC10蛋白)和不同截短体的EMC10蛋白。
二、鼠抗人EMC10的单克隆抗体4C2在治疗小鼠的脂肪肝的应用
将高脂饮食(饮食热量的60%来自脂肪)7周的体重为在35克左右的小鼠随机分为三组,即对照IgG组、对照1F12组和4C2抗体组,每组8-10只。4C2抗体组的每只小鼠以3mg/kg体重的剂量给予鼠抗人EMC10单克隆抗体4C2;对照1F12组的每只小鼠以3mg/kg体重的剂量给予鼠抗人EMC10单克隆抗体1F12;对照IgG组的每只小鼠以3mg/kg体重的剂量给予小鼠IgG。对照IgG组、1F12组和4C2抗体组每组每周均注射2次,共两周,过程中测量不同组小鼠的体重,不同组小鼠的体重和体重增加变化结果如图5中A和B所示,结果显示对照IgG组(图中以“IgG”表示)和1F12组(图中以“1F12”表示)的小鼠体重继续增长,而4C2抗体组(图中以“4C2”表示)小鼠的体重却出现了明显下降,2周内体重下降达到4克,其体重为负增长,与对照IgG组和1F12组相比有显著的统计学差异。
实验结束后(抗体治疗2周后),处死小鼠,称量对照IgG组、1F12组和4C2抗体组三组小鼠的肝脏重量,结果如图5中C所示,结果显示:不管是和对照IgG组(图中以“IgG”表示)还是和1F12组(图中以“1F12”表示)比较,4C2抗体组(图中以“4C2”表示)小鼠的肝脏重量均显著降低。
对照IgG组和4C2抗体组两组小鼠的肝脏组织进行切片HE染色,结果如图5中D所示,结果显示:对照IgG组(图中以“IgG”表示)小鼠的肝脏有大量的脂肪浸润,符合脂肪肝的表现,而4C2抗体组(图中以“4C2”表示)小鼠肝脏的脂肪浸润并不明显。
三、鼠抗人EMC10的单克隆抗体4C2在改善脂肪肝伴随的代谢紊乱中的应用
将高脂饮食7周的体重在35克左右的小鼠随机分为三组,即对照IgG组、对照1F12组和4C2抗体组,每组8-10只。4C2抗体组的每只小鼠以3mg/kg体重的剂量给予小鼠抗人EMC10单克隆抗体4C2;对照1F12组的每只小鼠以3mg/kg体重的剂量给予小鼠抗人EMC10单克隆抗体1F12;对照IgG组的每只小鼠以3mg/kg体重的剂量给予小鼠IgG。对照IgG组、1F12组和4C2抗体组每组每周均注射2次,共两周。采用经腹腔注射的胰岛素耐量实验(IPITT),给予对照IgG组、1F12组和4C2抗体组小鼠腹腔以每只小鼠以1mU/克体重的剂量注射胰岛素,分别监测0、30、60和90分钟的血糖,以注射前(0分钟)的血糖为100%,检测其余时间点血糖下降的百分数,检测三组小鼠的胰岛素耐量,结果如图6中A所示,结果显示:相比于对照IgG组(图中以“IgG”表示)和1F12组(图中以“1F12”表示),4C2治疗组(图中以“4C2”表示)小鼠的血糖在胰岛素注射后的15、30和90分钟均显著降低,说明4C2抗体能够显著改善脂肪肝伴随的胰岛素抵抗。研究结束后,处死小鼠分离血清,检测血清中胰岛素、甘油三酯、非酯化的脂肪酸以及胆固醇,结果如图6中B-E所示,结果显示:4C2治疗组(图中以“4C2”表示)小鼠相比于对照IgG组(图中以“IgG”表示)和1F12组(图中以“1F12”表示),血清甘油三酯和非酯化的脂肪酸均显著降低(图6中C和D),血清胰岛素和胆固醇也明显降低(图6中B和E)。
上述结果说明鼠抗人EMC10的单克隆抗体4C2能够显著降低肥胖小鼠的体重,并显著改善脂肪肝及其伴随的代谢紊乱,这为治疗脂肪肝等代谢性疾病提供了一个全新的治疗靶点。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
SEQUENCE LISTING
<110> 复旦大学附属华山医院
<120> 抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用
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gcgcccagtc gagcccgggg cagcggctgc cgggccggga ctggtgcgcg aggggctggg 120
gcggaaggtc gagagggcga ggcctgtggc acggtggggc tgctgctgga gcactcattt 180
gagatcgatg acagtgccaa cttccggaag cggggctcac tgctctggaa ccagcaggat 240
ggtaccttgt ccctgtcaca gcggcagctc agcgaggagg agcggggccg actccgggat 300
gtggcagccc tgaatggcct gtaccgggtc cggatcccaa ggcgacccgg ggccctggat 360
ggcctggaag ctggtggcta tgtctcctcc tttgtccctg cgtgctccct ggtggagtcg 420
cacctgtcgg accagctgac cctgcacgtg gatgtggccg gcaacgtggt gggcgtgtcg 480
gtggtgacgc accccggggg ctgccggggc catgaggtgg aggacgtgga cctggagctg 540
ttcaacacct cggtgcagct gcagccgccc accacagccc caggccctga gacggcggcc 600
ttcattgagc gcctggagat ggaacaggcc cagaaggcca agaaccccca ggagcagaag 660
tccttcttcg ccaaatactg gcacatcatc ctgggggggg ccgtgttgct cacagccctg 720
cgtcctgctg cgccagggcc cgcgccaccg ccacaggagg cctga 765
<210> 8
<211> 1380
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgagggcct ggatcttctt tctcctttgc ctggccggga gggctctggc agccccgcta 60
gcagaagtgc agctgttgga gtctggagga ggcttggtgc aacctggagg atccatgaaa 120
ctctcctgtg tagcctctgg atttattttc agtagttatt ggatgtcttg ggtccgccag 180
tctccagaaa aggggcttga gtgggttgct gaaattagat tgaaatctga taattatgaa 240
acacattatg cggagtctgt gaaagggaag ttcaccatct caagagatga ttccaaaagt 300
cgtctctacc tgcaaatgaa cagcttaaga gctgaagaca ctggaattta ttactgtacc 360
gatatggact actggggtca aggaacctca gtcaccgtct cctcagctaa aacgacaccc 420
ccatctgtct atccactggc ccctggatct gctgcccaaa ctaactccat ggtgaccctg 480
ggatgcctgg tcaagggcta tttccctgag ccagtgacag tgacctggaa ctctggatcc 540
ctgtccagcg gtgtgcacac cttcccagct gtcctgcagt ctgacctcta cactctgagc 600
agctcagtga ctgtcccctc cagcacctgg cccagcgaga ccgtcacctg caacgttgcc 660
cacccggcca gcagcaccaa ggtggacaag aaaattgtgc ccagggattg tggttgtaag 720
ccttgcatat gtacagtccc agaagtatca tctgtcttca tcttcccccc aaagcccaag 780
gatgtgctca ccattactct gactcctaag gtcacgtgtg ttgtggtaga catcagcaag 840
gatgatcccg aggtccagtt cagctggttt gtagatgatg tggaggtgca cacagctcag 900
acgcaacccc gggaggagca gttcaacagc actttccgct cagtcagtga acttcccatc 960
atgcacgagg actggctcaa tggcaaggag ttcaaatgca gggtcaacag tgcagctttc 1020
cctgccccca tcgagaaaac catctccaaa accaaaggca gaccgaaggc tccacaggtg 1080
tacaccattc cacctcccaa ggagcagatg gccaaggata aagtcagtct gacctgcatg 1140
ataacagact tcttccctga agacattact gtggagtggc agtggaatgg gcagccagcg 1200
gagaactaca agaacactca gcccatcatg gacacagatg gctcttactt cgtctacagc 1260
aagctcaatg tgcagaagag caactgggag gcaggaaata ctttcacctg ctctgtgtta 1320
catgagggcc tgcacaacca ccatactgag aagagcctct cccactctcc tggtaaatga 1380
<210> 9
<211> 459
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Arg Ala Trp Ile Phe Phe Leu Leu Cys Leu Ala Gly Arg Ala Leu
1 5 10 15
Ala Ala Pro Leu Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe
35 40 45
Ile Phe Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ser Pro Glu Lys
50 55 60
Gly Leu Glu Trp Val Ala Glu Ile Arg Leu Lys Ser Asp Asn Tyr Glu
65 70 75 80
Thr His Tyr Ala Glu Ser Val Lys Gly Lys Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Arg Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
100 105 110
Asp Thr Gly Ile Tyr Tyr Cys Thr Asp Met Asp Tyr Trp Gly Gln Gly
115 120 125
Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr
130 135 140
Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu
145 150 155 160
Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp
165 170 175
Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser
195 200 205
Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser
210 215 220
Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys
225 230 235 240
Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro
245 250 255
Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr
260 265 270
Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser
275 280 285
Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg
290 295 300
Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile
305 310 315 320
Met His Glu Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn
325 330 335
Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
340 345 350
Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu
355 360 365
Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe
370 375 380
Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala
385 390 395 400
Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr
405 410 415
Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly
420 425 430
Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His
435 440 445
Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455
<210> 10
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgagggcct ggatcttctt tctcctttgc ctggccggga gggctctggc agccccgcta 60
gcagatgttt tgatgaccca aactccactc tccctgcctg tcagtcttgg agatcaagcc 120
tccatctctt gcagatctag tcagagcctt gtacacagta atggaaacac ctatttacat 180
tggtacctgc agaagccagg ccagtctcca aagctcctga tctacaaagt ttccaaccga 240
ttttctgggg tcccagtcag gttcagtggc agtggatcag ggacagattt cacactcaag 300
atcagcagag tggaggctga ggatctggga gtttatttct gctctcaaag tatacatgtt 360
ccgtggacgt tcggtggagg caccaagctg gaaatcaaac gggcagatgc tgcaccaact 420
gtatccatct tcccaccatc cagtgagcag ttaacatctg gaggtgcctc agtcgtgtgc 480
ttcttgaaca acttctaccc caaagacatc aatgtcaagt ggaagattga tggcagtgaa 540
cgacaaaatg gcgtcctgaa cagttggact gatcaggaca gcaaagacag cacctacagc 600
atgagcagca ccctcacgtt gaccaaggac gagtatgaac gacataacag ctatacctgt 660
gaggccactc acaagacatc aacttcaccc attgtcaaga gcttcaacag gaatgagtgt 720
tag 723
<210> 11
<211> 240
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Met Arg Ala Trp Ile Phe Phe Leu Leu Cys Leu Ala Gly Arg Ala Leu
1 5 10 15
Ala Ala Pro Leu Ala Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu
20 25 30
Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln
50 55 60
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg
65 70 75 80
Phe Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr
100 105 110
Phe Cys Ser Gln Ser Ile His Val Pro Trp Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe
130 135 140
Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys
145 150 155 160
Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile
165 170 175
Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr
195 200 205
Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His
210 215 220
Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235 240
Claims (8)
1.抗人EMC10的单克隆抗体在制备治疗和/或预防脂肪肝的产品中的应用,其特征在于:所述单克隆抗体能特异性识别氨基酸序列如SEQ ID No.5所示的抗原表位;
所述抗人EMC10的单克隆抗体含有名称为VH的重链可变区和名称为VL的轻链可变区,所述VH和VL均由决定簇互补区和框架区组成;所述VH和所述VL的决定簇互补区均由CDR1、CDR2和CDR3组成;
所述VH的CDR1的氨基酸序列如SEQ ID No.1的第31-35位所示;
所述VH的CDR2的氨基酸序列如SEQ ID No.1的第50-68位所示;
所述VH的CDR3的氨基酸序列如SEQ ID No.1的第101-103位所示;
所述VL的CDR1的氨基酸序列如SEQ ID No.2的第24-39位所示;
所述VL的CDR2的氨基酸序列如SEQ ID No.2的第55-61位所示;
所述VL的CDR3的氨基酸序列如SEQ ID No.2的第94-102位所示。
2.根据权利要求1所述的应用,其特征在于:所述VH和VL的框架区均来源于小鼠。
3.根据权利要求1或2所述的应用,其特征在于:所述VH的氨基酸序列如SEQ ID No.1所示;所述VL的氨基酸序列如SEQ ID No.2所示。
4.根据权利要求1或2所述的应用,其特征在于:所述单克隆抗体为下述任一种:
S1)由所述VH和所述VL连接得到的单链抗体;
S2)含有所述VH和所述VL的Fab;
S3)含有所述VH和所述VL的完整抗体;
S4)由保藏号为CGMCC No.19950的杂交瘤细胞株4C2分泌的单克隆抗体。
5.与权利要求1-4中任一所述单克隆抗体相关的生物材料在制备治疗和/或预防脂肪肝的产品中的应用,其特征在于:所述生物材料为下述中的任一种:
A1)编码所述单克隆抗体的核酸分子;
A2)含有A1)所述核酸分子的表达盒;
A3)含有A1)所述核酸分子的重组载体、或含有A2)所述表达盒的重组载体;
A4)含有A1)所述核酸分子的重组微生物、或含有A2)所述表达盒的重组微生物、或含有A3)所述重组载体的重组微生物。
6.根据权利要求5所述的应用,其特征在于:A1)所述核酸分子为编码所述单克隆抗体的基因,所述基因为如下B1)或B2)所述的DNA分子:
B1)所述VH的CDR1的编码序列如SEQ ID No.3的第91-105位所示,所述VH的CDR2的编码序列如SEQ ID No.3的第148-204位所示,所述VH的CDR3的编码序列如SEQ ID No.3的第301-309位所示;所述VL的CDR1的编码序列如SEQ ID No.4的第70-117位所示,所述VL的CDR2编码序列如SEQ ID No.4的第163-183位所示,所述VL的CDR3的编码序列如SEQ ID No.4的第280-306位所示;
B2)与B1)限定的DNA分子具有90%以上的同一性且编码所述单克隆抗体或其抗原结合部分的DNA分子。
7.权利要求1-4中任一所述的单克隆抗体或权利要求5或6中所述的生物材料在下述任一中的应用:
C1)在制备降低动物的肝脏的脂肪浸润的产品中的应用;
C2)在制备降低动物的血清甘油三酯含量的产品中的应用;
C3)在制备降低动物的血清游离脂肪酸含量的产品中的应用;
C4)在制备降低动物的血清胆固醇含量的产品中的应用。
8.根据权利要求1或2或5或6或7所述的应用,其特征在于:所述产品为药物、试剂或试剂盒。
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